Brilinta 90mg

Brilinta 90mg is indicated for the prevention of thrombotic events (cardiovascular death, myocardial infarction and stroke) in patients with Acute Coronary Syndromes [(ACS) unstable angina, non ST elevation Myocardial Infarction (NSTEMI) or ST elevation Myocardial Infarction (STEMI)] including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG).

Brilinta 90mg is used alone or together with aspirin to lessen the chance of heart attack, stroke, or other serious problems with your heart or blood vessels. It is given to patients who have already had a heart attack or severe chest pain, stroke, or to people with other blood circulation problems that could lead to a stroke or heart attack.

A heart attack or stroke may occur when a blood vessel in the heart or brain is blocked by a blood clot. Brilinta 90mg reduces the chance that a harmful blood clot will form by preventing certain cells in the blood from clumping together. This effect of Brilinta 90mg may also increase the chance of serious bleeding in some people.

Brilinta 90mg is available only with your doctor's prescription.

Brilinta 90mg treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.

For oral use. Brilinta 90mg can be taken with or without food. For patients who are unable to swallow the tablet(s) whole, Brilinta 90mg tablets (90 mg and 2 x 90 mg) can be crushed to a fine powder and mixed in half a glass of water and drunk immediately. The glass should be rinsed with a further half glass of water and the contents drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater). It is important to flush the nasogastric tube through with water after administration of the mixture.

Patients taking Brilinta 90mg should also take Acetylsalicylic Acid/Aspirin (ASA) daily unless specifically contraindicated. Following an initial dose of ASA, Brilinta 90mg should be used with a maintenance dose of ASA of 75-150 mg.

Lapses in therapy should be avoided. A patient who misses a dose of Brilinta 90mg should take one 90 mg tablet (their next dose) at its scheduled time.

Physicians who desire to switch patients from clopidogrel to Brilinta 90mg should administer the first 90 mg dose of Brilinta 90mg 24 hours following the last dose of clopidogrel.

Treatment is recommended for at least 12 months unless discontinuation of Brilinta 90mg is clinically indicated. In patients with Acute Coronary Syndromes (ACS), premature discontinuation with any antiplatelet therapy, including Brilinta 90mg, could result in an increased risk of cardiovascular death, or myocardial infarction due to the patient’s underlying disease.

Special Populations: Paediatric Patients: Safety and efficacy in children below the age of 18 have not been established.

Elderly Patients: No dose adjustment is required.

Patients with Renal Impairment: No dose adjustment is necessary for patients with renal impairment. No information is available concerning treatment of patients on renal dialysis.

Patients with Hepatic Impairment: No dose adjustment is necessary for patients with mild hepatic impairment. Brilinta 90mg has not been studied in patients with moderate or severe hepatic impairment.

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What is the most important information I should know about Brilinta 90mg?

Brilinta 90mg keeps your blood from coagulating (clotting) to prevent unwanted blood clots that can occur with certain heart or blood vessel conditions. Because of this drug action, Brilinta 90mg can make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

You may also have bleeding on the inside of your body, such as in your stomach or intestines. Call your doctor at once if you have black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds. These could be signs of bleeding in your digestive tract.

While you are taking Brilinta 90mg, do not take aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) without your doctor's advice. NSAIDs include ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Cataflam, Voltaren), indomethacin (Indocin), meloxicam (Mobic), and others.

Brilinta 90mg may cause you to bleed more easily, especially if you have: a history of bleeding problems, surgery or a medical emergency, a disease affecting the blood vessels in your brain, a history of stomach or intestinal bleeding, or if you are 65 or older.

Many drugs (including some over-the-counter medicines and herbal products) can interact with Brilinta 90mg. It is very important to tell your doctor about all medicines you have recently used.

Ask your doctor before taking any medicine for pain, arthritis, fever, or swelling. These medicines may affect blood clotting and may also increase your risk of stomach bleeding.

Any doctor, dentist, surgeon, or other medical care provider who treats you should know that you are taking Brilinta 90mg.

Use Brilinta 90mg as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Brilinta 90mg comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Brilinta 90mg refilled.
• Take Brilinta 90mg by mouth with or without food.
• Take Brilinta 90mg on a regular schedule to get the most benefit from it.
• If you miss a dose of Brilinta 90mg, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Brilinta 90mg.

Use: Labeled Indications

Acute coronary syndrome: Reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. Brilinta 90mg also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

Off Label Uses

Non-ST-elevation acute coronary syndrome, aspirin intolerant patients

Based on the American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), Brilinta 90mg is a reasonable alternative to aspirin in aspirin intolerant patients even though it has not been studied in the absence of aspirin.

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What other drugs will affect Brilinta 90mg?

Effects of Other Drugs on Brilinta 90mg: Medicinal Products Metabolised by CYP3A4: Ketoconazole (Strong CYP3A4 Inhibitors): Co-administration of ketoconazole with Brilinta 90mg increased Brilinta 90mg C_max and AUC equal to 2.4-fold and 7.3-fold, respectively. The C_max and AUC of the active metabolite were reduced by 89% and 56% respectively. Other strong inhibitors of CYP3A4 (clarithromycin, nefazodone, ritonavir, and atazanavir) would be expected to have similar effects and should not be given concomitantly with Brilinta 90mg.

Diltiazem (Moderate CYP3A4 Inhibitors): Co-administration of Brilinta 90mg and diltiazem increased the C_max of Brilinta 90mg by 69% and AUC by 174% and decreased the active metabolite C_max by 38% and AUC was unchanged. There was no effect of Brilinta 90mg on diltiazem plasma levels. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, erythromycin, fluconazole, and verapamil) can as well be co-administered with Brilinta 90mg.

Rifampin and Other CYP3A Inducers: Co-administration of rifampin with Brilinta 90mg decreased Brilinta 90mg C_max and AUC by 73% and 86%, respectively. The C_max of the active metabolite was unchanged and the AUC was decreased by 46% respectively. Other CYP3A4 inducers (e.g. phenytoin, carbamazepine and phenobarbital) would be expected to decrease the exposure to Brilinta 90mg as well and may result in reduced efficacy of Brilinta 90mg.

Cyclosporine (PgP and CYP3A Inhibitor): Co-administration of cyclosporine (600 mg) with Brilinta 90mg increased Brilinta 90mg C_max and AUC equal to 2.3-fold and 2.8-fold, respectively. The AUC of the active metabolite was increased by 32% and C_max was decreased by 15% in the presence of cyclosporine. There was no effect of Brilinta 90mg on cyclosporine blood levels.

Others: Clinical pharmacology interaction studies showed that co-administration of Brilinta 90mg with heparin, enoxaparin and aspirin did not have any effect on Brilinta 90mg or the active metabolite plasma levels. Co-administration of Brilinta 90mg and heparin had no effect on heparin based on activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) assays. Co-administration of Brilinta 90mg and enoxaparin had no effect on enoxaparin based on factor Xa assay.

Effects of Brilinta 90mg on Other Drugs: Medicinal Products Metabolised by CYP3A4: Simvastatin: Co-administration of Brilinta 90mg with simvastatin increased simvastatin C_max by 81% and AUC by 56% and increased simvastatin acid C_max by 64% and AUC by 52% with some individual increases equal to 2 to 3 fold. Consideration of the clinical significance should be given to the magnitude and range of changes on the exposure to patients requiring greater than 40 mg of simvastatin. There was no effect of simvastatin on Brilinta 90mg plasma levels. Brilinta 90mg may have similar effect on lovastatin, but is not expected to have a clinically meaningful effect on other statins.

Atorvastatin: Co-administration of atorvastatin and Brilinta 90mg increased atorvastatin acid C_max by 23% and AUC by 36%. Similar increases in AUC and C_max were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant.

Medicinal Products Metabolised by CYP2C9: Tolbutamide: Co-administration of Brilinta 90mg with tolbutamide resulted in no change in the plasma levels of either drug, which suggest that Brilinta 90mg is not a CYP2C9 inhibitor and unlikely to alter the CYP2C9 mediated metabolism of drugs like warfarin and tolbutamide.

Oral Contraceptives: Co-administration of Brilinta 90mg and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the PK of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are co-administered with Brilinta 90mg.

Digoxin (PgP Substrate): Concomitant administration of Brilinta 90mg increased the digoxin C_max by 75% and AUC by 28%. Therefore, appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent drugs like digoxin concomitantly with Brilinta 90mg.

Other Concomitant Therapy: In clinical studies, Brilinta 90mg was commonly administered with acetylsalicylic acid, heparin, low molecular weight heparin, intravenous GpIIb/IIIa inhibitors, proton pump inhibitors, statins, beta-blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers as needed for concomitant conditions. These studies did not produce any evidence of clinically significant adverse interactions.

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What are the possible side effects of Brilinta 90mg?

Summary of the Safety Profile: The safety profile of Brilinta 90mg has been evaluated in two large phase 3 outcome trials (PLATO and PEGASUS) including more than 39,000 patients.

The relevant adverse drug reactions observed in these studies are discussed below.

The safety of Brilinta 90mg in patients with acute coronary syndromes (UA, NSTEMI and STEMI) was evaluated in the PLATO study, which compared patients treated with Brilinta 90mg 90 mg twice daily to patients treated with clopidogrel 75 mg once daily both given in combination with ASA and other standard therapies. Median treatment duration for Brilinta 90mg was 277 days. In PLATO patients on Brilinta 90mg had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%).

The safety of Brilinta 90mg in patients with history of MI (MI occurred at least one year ago) and high risk of developing a thrombotic event was evaluated in the PEGASUS study, which compared patients treated with Brilinta 90mg 60 mg twice daily or 90 mg twice daily combined with ASA to ASA therapy alone and other standard therapies.

The most commonly reported adverse drug reactions in patients treated with Brilinta 90mg were bleeding and dyspnoea.

Tabulated List of Adverse Drug Reactions: Adverse drug reactions from the PLATO and PEGASUS clinical studies with Brilinta 90mg (Table 2) are listed by MedDRA System Organ Class (SOC) and frequency category. Within each SOC and frequency category, adverse drug reactions are presented in order of decreasing seriousness. Frequency categories are defined according to the following conventions: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Description of Selected Adverse Drug Reactions: Bleeding: The following bleeding definitions were used in the PLATO study.

'Major Fatal/Life-threatening': Fatal, or intracranial, or intrapericardial bleed with cardiac tamponade, or hypovolaemic shock or severe hypotension due to bleeding and requiring pressors or surgery, or clinically overt or apparent bleeding associated with a decrease in haemoglobin of more than 50 g/L, or transfusion of 4 or more units (whole blood or PRBCs) for bleeding.

'Major Other': Significantly disabling (e.g., intraocular with permanent vision loss), or clinically overt or apparent bleeding associated with a decrease in haemoglobin of 30 to 50 g/L, or transfusion of 2-3 units (whole blood or PRBCs) for bleeding.

'Minor': Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).

Minimal bleeds included all other bleeds; these were collected but not adjudicated.

Bleeding events reported in PLATO were also mapped to the TIMI (Thrombolysis in Myocardial Infarction) scale, to facilitate comparison with other similar studies. TIMI Major is defined as clinically overt bleeding associated with a fall in haemoglobin >50 g/L, or intracranial hemorrhage, and TIMI Minor is defined as overt bleeding associated with a fall in haemoglobin of 30 g/L but ≤50 g/L.

Overall outcome of bleeding events in the PLATO study are shown in Figure 4 and Table 3.

In PLATO, time to first PLATO-defined 'Total Major' bleeding for Brilinta 90mg did not differ significantly from that of clopidogrel. There were few fatal bleeding events in the study, 20 (0.2%) for Brilinta 90mg 90 mg twice daily and 23 (0.3%) for clopidogrel 75 mg once daily. When minor bleeding was included, combined PLATO-defined Major and Minor bleeding events were significantly higher on Brilinta 90mg than on clopidogrel. Overall rates of TIMI-defined bleeding events did not differ significantly between Brilinta 90mg and clopidogrel.

CABG-Related Bleeding: In PLATO, 1584 patients (12%) underwent coronary artery bypass graft (CABG) surgery. 'Major Fatal/Life-threatening' bleeding was approximately 42% in both treatment groups. There was no difference between the treatment groups with respect to risk of 'Major Fatal/Life-threatening' CABG bleeding relative to time of last dose before the procedure. Fatal CABG bleeding occurred uncommonly, 6 patients in each treatment group (0.8% and 0.7% of CABG patients on Brilinta 90mg and clopidogrel, respectively).

Non-CABG Related Bleeding: When CABG bleeding is removed from the analysis, the absolute bleeding rates for all categories are lower. The groups did not differ in non-CABG PLATO-defined Major Fatal/Life-threatening bleeding, but PLATO-defined 'Total Major', TIMI Major, and TIMI Major + Minor bleeding was more common with Brilinta 90mg.

Bleeding Unrelated to Any Procedure: As shown in Table 3 PLATO-defined 'Major' and 'Major + Minor' non-procedural bleeding was more frequent with Brilinta 90mg. Discontinuation of treatment due to non-procedural bleeding was more common for Brilinta 90mg (2.9%) than for clopidogrel (1.2%; p<0.001). Clinically important locations for 'Major + Minor' bleeding in rank order by frequency were (Brilinta 90mg vs clopidogrel): Intracranial (27 vs 14 events), pericardial (11 vs 11), retroperitoneal (3 vs 3), intraocular (2 vs 4) and intra-articular (2 vs 1). Other common locations were in rank order of frequency: gastrointestinal (170 vs 135 events), epistaxis (116 vs 61), urinary (45 vs 37), subcutaneous/dermal (43 vs 38) and haemoptysis (13 vs 7).

There was no difference with Brilinta 90mg compared to clopidogrel for fatal non-procedural bleeding. 'Major Fatal/Life-threatening' gastrointestinal bleeding was the same with Brilinta 90mg and clopidogrel, with numerically more fatal events for clopidogrel (5) than for Brilinta 90mg (none). There were numerically more 'Major Fatal/Life-threatening' intracranial non-procedural bleeding events with Brilinta 90mg (n=27 events in 26 patients, 0.3%) than with clopidogrel (n=14 events, 0.2%), of which 11 bleeding events with Brilinta 90mg and 1 with clopidogrel were fatal.

Baseline characteristics including age, gender, weight, race, geographic region, medical history, concurrent conditions and concomitant therapy were assessed to explore any increase in risk of bleeding with Brilinta 90mg. No particular risk group was identified for any subset of bleeding.

Dyspnoea: In PLATO dyspnoea adverse events were reported in 13.8% of patients taking Brilinta 90mg 90 mg twice daily and in 7.8% in patients taking clopidogrel 75 mg once daily. Most reported dyspnoea adverse events were mild to moderate in intensity and often resolved without the need of treatment discontinuation. Dyspnoea was usually reported in the initial phase of treatment and 87% of the patients who reported dyspnoea experienced a single episode. Dyspnoea serious adverse events were reported in 0.7% taking Brilinta 90mg and 0.4% taking clopidogrel. Patients who reported dyspnoea tended to be older and more frequently had dyspnoea, CHF, COPD, or asthma at baseline. PLATO data do not suggest that the higher frequency with Brilinta 90mg is due to new or worsening heart or lung disease. There was no indication of an adverse effect of Brilinta 90mg on pulmonary function.

Lab Abnormalities: In PLATO, serum uric acid concentration increased to more than upper limit of normal in 22% of patients receiving Brilinta 90mg compared to 13% of patients receiving clopidogrel. Mean serum uric acid concentration increased approximately 15% with Brilinta 90mg compared to approximately 7% with clopidogrel and reduced after treatment was stopped. There was no difference in the frequency of clinical adverse events.

In PLATO, serum creatinine concentration increased by >50% in 8% of patients receiving Brilinta 90mg compared to 7% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Signs of reversibility on discontinuation were observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for related serious adverse events.

Brilinta 90mg (trade name Brilinta 90mg in the US, Brilique and Possia in the EU) is a platelet aggregation inhibitor produced by AstraZeneca. Unlike clopidogrel, Brilinta 90mg is not a prodrug and does not require metabolic activation. The drug was approved for use in the European Union by the European Commission on December 3, 2010. The drug was approved by the US Food and Drug Administration on July 20, 2011.